The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial

Youssef et al., Critical Care Medicine, doi:10.1097/CCM.0000000000005660, COVID-AIV, NCT04311697, Aug 2022

https://c19early.org/youssef.html

RCT 196 patients with critical COVID-19 respiratory failure showing improved survival but no significant difference in the primary endpoint of "alive and free of respiratory failure at day 60" with IV aviptadil.

Standard of Care (SOC) for COVID-19 in the study country, the USA, is very poor with very low average efficacy for approved treatments1. Only expensive, high-profit treatments were approved. Low-cost treatments were excluded, reducing the probability of treatment—especially early—due to access and cost barriers, and eliminating complementary and synergistic benefits seen with many low-cost treatments. This may explain in part the very high mortality seen in this study. Results may differ in countries with improved SOC.

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risk of death, 35.0% lower, RR 0.65, p = 0.04, treatment 46 of 131 (35.1%), control 30 of 65 (46.2%), NNT 9.1, inverted to make RR<1 favor treatment, odds ratio converted to relative risk, day 60.

risk of progression, 20.1% lower, RR 0.80, p = 0.27, treatment 59 of 131 (45.0%), control 31 of 65 (47.7%), inverted to make RR<1 favor treatment, odds ratio converted to relative risk, respiratory failure or death, day 60, primary outcome.

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1. c19early.org, c19early.org/soc/usa.html.c19early.org/soc/usa.html.

Youssef et al., 29 Aug 2022, Double Blind Randomized Controlled Trial, placebo-controlled, USA, peer-reviewed, 10 authors, study period 15 May, 2020 - 24 December, 2020, trial NCT04311697 (history) (COVID-AIV).

This Paper Aviptadil All

The Use of IV Vasoactive Intestinal Peptide (Aviptadil) in Patients With Critical COVID-19 Respiratory Failure: Results of a 60-Day Randomized Controlled Trial*

MD Jihad Georges Youssef, PhD Philip Lavin, PhD David A Schoenfeld, MD Richard A Lee, MD Rainer Lenhardt, MD David J Park, Javier Perez Fernandez, MD Melvin L Morganroth, MD, MPH Jonathan C Javitt, MD Dushyantha Jayaweera

Critical Care Medicine, doi:10.1097/ccm.0000000000005660

OBJECTIVES: Respiratory failure is a lethal complication of COVID-19 that has remained resistant to drug therapy. Vasoactive intestinal peptide (VIP) is shown in nonclinical studies to upregulate surfactant production, inhibit cytokine synthesis, prevent cytopathy, and block replication of the severe acute respiratory syndrome coronavirus 2 virus in pulmonary cells. The study aims to determine whether Aviptadil (synthetic VIP) can improve survival and recovery in patients with COVID-19 respiratory failure compared with placebo and demonstrate biological effects in such patients. DESIGN: A multicenter, placebo-controlled trial. SETTING: Ten U.S. hospitals: six tertiary-care hospitals and four community hospitals. PATIENTS: A total of 196 patients with COVID-19 respiratory failure. INTERVENTIONS: Participants were randomized 2:1 to receive 3 days of IV Aviptadil or placebo. MEASUREMENTS AND MAIN RESULTS: The primary end point (alive and free from respiratory failure at day 60) did not reach statistical significance (odds ratio [OR], 1.6; 95% CI, 0.86-3.11) for patients treated with Aviptadil when controlling for baseline ventilation status as prespecified in the protocol. There was, however, a statistically significant two-fold odds of improved survival (OR, 2.0; 95% CI, 1.1-3.9) at 60 days (p = 0.035). There was significant improvement in respiratory distress ratio and reduced interleukin 6 cytokine release (p = 0.02) by day 3. Subgroup analysis identified a statistically significant likelihood of achieving primary end point among those treated with high-flow nasal oxygen at baseline (p = 0.039). Subjects on mechanical ventilation also experienced a 10-fold increased odds of survival with drug versus placebo (p = 0.031). CONCLUSIONS: The primary end point did not reach statistical significance, indicating that there was no difference between Aviptadil versus placebo. However, Aviptadil improves the likelihood of survival from respiratory failure at day 60 in critical COVID-19 across all sites of care. Given the absence of drug-related serious adverse events and acceptable safety profile, we believe the benefit versus risk for the use of Aviptadil is favorable for patient treatment.

References

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Bravata, Perkins, Myers, Association of intensive care unit patient load and demand with mortality rates in US department of veterans affairs hospitals during the COVID-19 pandemic, JAMA Netw Open

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Gorham, Moreau, Corazza, Interleukine-6 in critically ill COVID-19 patients: A retrospective analysis, PLoS One

Javitt, Youssef, VIP: A COVID-19 Therapeutic That Blocks Coronavirus Replication

Jihad, Sami, George, Treatment of acute respiratory distress syndrome with vasoactive intestinal peptide, J Infect Dis Treat

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Li, Luo, Zhou, Effect of vasoactive intestinal peptide on pulmonary surfactants phospholipid synthesis in lung explants, Acta Pharmacol Sin

Li, She, Yue, Role of c-fos gene in vasoactive intestinal peptide promoted synthesis of pulmonary surfactant phospholipids, Regul Pept

Mason, Pathogenesis of COVID-19 from a cell biologic perspective, Eur Respir J

Petkov, Mosgoeller, Ziesche, Vasoactive intestinal peptide as a new drug for treatment of primary pulmonary hypertension, J Clin Invest

Prasse, Zissel, Lützen, Inhaled vasoactive intestinal peptide exerts immunoregulatory effects in sarcoidosis, Am J Respir Crit Care Med

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Youssef, Javitt, Lavin, VIP in the treatment of critical COVID-19 with respiratory failure in patients with severe comorbidity: A prospective externally controlled, J Infect Dis Treat

Zwarenstein, Treweek, Gagnier, Pragmatic Trials in Healthcare (Practihc) group: Improving the reporting of pragmatic trials: An extension of the CONSORT statement, BMJ

DOI record: { "DOI": "10.1097/ccm.0000000000005660", "ISSN": [ "0090-3493" ], "URL": "http://dx.doi.org/10.1097/CCM.0000000000005660", "abstract": "\n OBJECTIVES:\n Respiratory failure is a lethal complication of COVID-19 that has remained resistant to drug therapy. Vasoactive intestinal peptide (VIP) is shown in nonclinical studies to upregulate surfactant production, inhibit cytokine synthesis, prevent cytopathy, and block replication of the severe acute respiratory syndrome coronavirus 2 virus in pulmonary cells. The study aims to determine whether Aviptadil (synthetic VIP) can improve survival and recovery in patients with COVID-19 respiratory failure compared with placebo and demonstrate biological effects in such patients.\n \n \n DESIGN:\n A multicenter, placebo-controlled trial.\n \n \n SETTING:\n Ten U.S. hospitals: six tertiary-care hospitals and four community hospitals.\n \n \n PATIENTS:\n A total of 196 patients with COVID-19 respiratory failure.\n \n \n INTERVENTIONS:\n Participants were randomized 2:1 to receive 3 days of IV Aviptadil or placebo.\n \n \n MEASUREMENTS AND MAIN RESULTS:\n The primary end point (alive and free from respiratory failure at day 60) did not reach statistical significance (odds ratio [OR], 1.6; 95% CI, 0.86–3.11) for patients treated with Aviptadil when controlling for baseline ventilation status as prespecified in the protocol. There was, however, a statistically significant two-fold odds of improved survival (OR, 2.0; 95% CI, 1.1–3.9) at 60 days (p = 0.035). There was significant improvement in respiratory distress ratio and reduced interleukin 6 cytokine release (p = 0.02) by day 3.\n Subgroup analysis identified a statistically significant likelihood of achieving primary end point among those treated with high-flow nasal oxygen at baseline (p = 0.039). Subjects on mechanical ventilation also experienced a 10-fold increased odds of survival with drug versus placebo (p = 0.031).\n \n \n CONCLUSIONS:\n The primary end point did not reach statistical significance, indicating that there was no difference between Aviptadil versus placebo. However, Aviptadil improves the likelihood of survival from respiratory failure at day 60 in critical COVID-19 across all sites of care. 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